During the past year, there have been two areas of research ongoing in the Molecular Immunology Section: 1) identification of proinflammatory functions of CD8+ cytotoxic T cells in multiple sclerosis and HTLV-I- associated myelopathy/tropical spastic paraparesis; and 2) identification of structure/function relationships of human CD8+ T cell antigen-specific receptors. The focus of research on the proinflammatory roles of CD8+ cytotoxic T cells has primarily addressed the following question: in addition to the demonstrated function of antigen-specific killing of appropriate target cells, can these cytotoxic T cells secrete soluble mediators that promote and maintain an inflammatory response? The answer is yes, since we have been able to demonstrate that these T cells are triggered by specific antigen to secrete at least three broad categories of proinflammatory mediators: cytokines, chemokines (chemotactic cytokines), and matrix metalloproteinases. Future efforts are focused on the assessment of the presence of these proinflammatory mediators in disease states, and their effects on specific immune functions. Collaborative studies have produced the first crystallographic structure of a trimolecular complex of a CD8+ T cell antigen-specific receptor complexed with a viral peptide/MHC molecule. Based on this structure, we have been able to identify specific amino acid side chains of the bound peptide that interact with the T cell receptor. When these amino acid side chains are substituted with other side chains, they can produce significant changes in the functional readout of the T cell when its receptor is engaged. We have begun to exploit these observations to permit a detailed analysis of the signal transduction pathways that are responsible for receptor-mediated effector functions. So far, we have identified the ERK MAPkinase pathway of activation as critical for T cell receptor signal transduction, and that different functional readouts correlate with sustained, versus transient activation of this pathway. In addition, a novel protein kinase C-dependent feedback inhibition pathway mediated by a cell lineage-specific phosphatase has also been identified. Future experiments will be designed to provide more detailed analysis of this feedback inhibition pathway, and identification of its possible involvement in producing different effector functions of CD8+ T cells.